Fatty liver disease and liver fibrosis can be chronic liver diseases and represent a common and difficult clinical challenge of worldwide importance. Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation.
Non-alcoholic steatohepatitis (NASH) is a severe form of fatty liver disease that affects 2 to 5 percent of Americans. It resembles alcoholic liver disease but occurs in people who drink little or no alcohol. The major feature of NASH is excess fat contentin the liver, along with inflammation and liver damage. NASH can lead to liver cirrhosis, fibrosis, hepatocellular carcinoma, liver failure, liver-related death, and liver transplantation. NASH can also lead to an increased risk of cardiovascular disease.
Although NASH affects only 2-5% of Americans, it is becoming prevalent, likely because of the greater number of Americans with obesity. Many people with NASH are middle-aged, obese, diabetic and/or have elevated blood cholesterol levels. However, NASH can occur in people without any apparent risk factor and can even occur in children. Currently, there are no specific therapies for treating NASH, although some studies suggest that diet, exercise and reducing alcohol intake may be useful in altering the course of the disease.
At present, the only curative treatment for end stage cirrhosis is transplantation, but limited availability of donor organs and the clinical condition of the potential recipient limit the applicability of this technique.
MetAP2 encodes a protein that functions at least in part by enzymatically removing the amino terminal methionine residue from certain newly translated proteins such as glyceraldehyde-3-phosphate dehydrogenase (Warder et al. (2008) J Proteome Res 7:4807). Increased expression of the MetAP2 gene has been historically associated with various forms of cancer. Molecules inhibiting the enzymatic activity of MetAP2 have been identified and have been explored for their utility in the treatment of various tumor types (Wang et al. (2003) Cancer Res. 63:7861) and infectious diseases such as microsporidiosis, leishmaniasis, and malaria (Zhang et al. (2002) J. Biomed. Sci. 9:34). Notably, inhibition of MetAP2 activity in obese and obese-diabetic animals leads to a reduction in body weight in part by increasing the oxidation of fat and in part by reducing the consumption of food (Rupnick et al. (2002) Proc. Natl. Acad. Sci. USA 99:10730).